Androstane-16, 17-dicarboxylic acid imides



aired tat Pte 3,071,578 ANDROSTANE-i6,1l7-DICOXYLIC ACED IMHDES Pierre (Irahh, Mexico (Iity, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed .lnly 19, 1961, Ser. No. 125,106

19 Qlaims. (ill. 260-2395) In the above formulas Z represents a double bond for a saturated linkage between C4 and C5; Y represents a double bond or a saturated linkage between C-5 and 0-6; X represent the group in the doling-positions, wherein R may be hydrogen, a lower alkyl, di(lower alkyl) amino, lower alkyl, aryl or aralkyl group, each containing up to 8 carbon atoms; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, aeyioxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fl-chloropropionate.

The novel compounds of the present invention are pre- Patented Jan. 1, 1953 $12, o any iii, Cm m to @x In the above formulas R has the same meaning as hereinabove set forth; Ac represents an acyl group, preferably the acetyl group. 1

In practicing the process outlined above the starting compound (I) 16a-cyano-A -pregnen-3,8-ol-20-one 3-acetate [1. Romo, Tetrahedron 3, 37 (1958)], is hydrolyzed in a basic medium, such as methanolic potassium hydroxide, affording A -17a-pregnen-3fl-ol-20-one-lGB-carboxylic acid (II). This compound is treated with an alkali metal hypohalogenite such as sodium hypobromite at a lower temperature, approximately C., for a period of time of the order of 2 hours, thus giving A -androsten- 3,6-01-165,17,3-dicarboxylic acid (III). Upon reflux of this compound with acetic anhydride there is obtained the anhydride of A -androsten-3fi-ol-16B,'17,B-dicarboxylic acid 3-acetate (IV).

Alternatively the starting compound (I) is treated with an alkali metal hypohalogenite, such as sodium hypobrornite, at a low temperature, approximately 0 C., for a period of time of the order of 2 hours, thus furnishing l6a-cyano-A -androsten-3,B-ol-l7fi-carboxylic acid 3-acetate (IX). Hydrolysis of this compound in a basic medium such as methanolic potassium hydroxide, affords the above obtained A -androsten-3B-ol- 1613,17fl-dicarboxylic acid (III).

The anhydride of A -andr0sten-3/8-o1-1618,17fl-dicarboxylic acid 3-acetate compound (IV) is treated with a primary amine, as for example, methylamine, ethylamine, propylamine, aniline, benzylamine or ammonia, thus giving the corresponding A5-androsten-3fi-ol-l6p,17,8 dicarboxylic acid imide 3-acetate derivative (V) which upon saponification in a mild alkaline medium, such as potassium carbonate solution, affords the corresponding free 3,8-alcohol (VI). This free alcohol is oxidized under Oppenauer conditions to the corresponding A -androsten- 3-one-16fl,17fi-dicarboxylic acid amide derivative (VII) which is hydrogenated to the respective saturated 3-ketone androstane (VIII).

The A -313-alcoho1 derivative (VI) is hydrogenated to the corresponding androstan-3l3-ol-l 6fi,17fl-dicarboxylic acid amide derivative.

The above obtained compounds containing a free secondary hydroxyl group at C-3 are conventionally acylated in pyridine with a hydrocarbon carboxylic acid anhydride or chloride containing up to 12 carbon atoms of the type mentioned previously to furnish the corresponding 35- acyloxy derivative.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I 5 g. of 16a-cyano-A -pregnen-3,8-ol-2O-one 3-acetate [1. Romo, Tetrahedron 3, 37 (1958)], were dissolved in 200 cc. of dioxane. A solution, prepared by dissolving 7 g. of sodium hydroxide in 60 cc. of water and 40 cc. of dioxane and further adding dropwise 3.2 cc. of bromine, was added to the steroid solution, the operation being conducted at 5 C. The resulting mixture was stirred for 2 hours, maintaining the temperature under 5 C. It was then treated with 50 cc. of a saturated solution of sodium sulfite in water, refluxed for 15 minutes, acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness thus affording 16a-cyano A androsten-Bfi-ol-17,8-carboxylic acid B-acetate. M.P. 259261 C.; [04] -62 (pyridine). By alkaline hydrolysi the 3fi-alcohol was obtained: M.P. 271274; [oc] -71 (pyridine).

The foregoing compound was refluxed for hours with 250 cc. of 4% methanolic potassium hydroxide solution and then neutralized with acetic acid. Part of the solvent was removed under reduced pressure and the concentrated solution poured into water. The formed precipitate was filtered off, washed with water and dried in vacuo. Recrystallization from acetone-hexane afforded A -androsten-3 8-ol-l6/3,17,8-dicarboxylic acid. M.P. 312- 314 C.; [oc] 63 (pyridine).

Example II By reversing the steps described in the preceding Example, 5 g. of 16u-cyano-A -pregnen-3fl-ol-ZO-one 3-acetate was first hydrolyzed with 4% methanolic potassium hydroxide as described in Example I to afford A -17ocpregnen-B/i-ol-ZO-one-16/3-carboxylic acid, identical with an authentic specimen.

Upon further treatment with sodium hydroxide and bromine as described in Example I and working up the product as set forth in that example, there was afforded A -androsten-3B-ol-165,17,8-dicarboxylic acid. M.P. 307- 309 0., identical with the above obtained diacid.

Example III The foregoing compound, A -androsten-3fi-ol-16fl,17,9- dicarboxylic acid was refluxed for 10 minutes with 60 cc. of acetic anhydride. 'Ihe acetic anhydride was then evaporated under vacuum and the residue recrystallized from methylene-chloride-hexane affording the anhydride of the A -androsten-3 8-ol-16p,17,8-dicarboxylic acid 3- acetate. M.P. 171-175 C.; [1x1 83 (CHCl Example IV 2 g. of this last anhydride was treated with a solution of 2 g. of propylamine in methylene chloride. The reaction mixture was allowed to-stand at room temperature overnight. The solvent was then evaporated and the residue recrystallized from acetone-hexane affording N- propyl-A -androsten-3 8-ol-16,8,17,8-dicar-boxylic acid imide 3-acetate.

Example V 2 g. of the anhydride of A -androsten-3 3ol-l6fi,17;8-dicarboxylic acid 3-acetate was treated following the technique described in Example IV except that propylamine was substituted by N,N-diethylamino-ethylamine, giving N (N',N' diethylaminoethyl)-A -androsten-3fi-ol-16B, 17,6-dicarboxylic acid imide 3-acetate.

Example VI 2 g. of the anhydride of A -androsten-3B-ol-16fi,17,8- dicarboxylic acid 3-acetate was treated following the technique described in Example IV except that propyl amine was substituted by aniline affording N-phenyl-A androsten-3fi-ol-165,175-dicarboxylic acid imide 3-acetate.

Example VII 2 g. of the anhydride of A -androsten-3fi-ol-16 8,17fldicarboxylic acid 3-acetate were treated with 50 cc. of a saturated solution of ammonia in anhydrous ethanol. The reaction mixture was kept in a closed vessel at room temperature for 24 hours. It was then evaporated to dryness and the residue recrystallized from acetone thus affording A androsten-3fl-ol-l6fl,l7fi-dicarboxylic acid imide 3-acetate.

Example VIII A -androsten-3fi-ol-1613,1713-dicarboxylic acid imide 3-acetate, there were respectively obtained A -androsten-3fi-ol- 165,175-dicarboxylic acid imide, N-propyl-M-androsten- 35-01-16fl,17/3-dicarboxylic acid imide, N-(N,N'-diethylaminoethyl)-A -androsten-3,8-ol165,17fl-dicarboxylic acid imide and N-phenyl-A -androsten-318-01-16,8,l7fi-dicarb0xylic acid imide.

Example IX A solution of 1 g. of A -androsten-3/3-ol-16,8,17fi-dicarboxylic acid imide in 80 cc. of toluene and 20 cc. of cyclohexanone was dried by distilling oif cc. of the solvent. A solution of 1 g. of aluminum isopropoxide in 7 cc. of anhydrous toluene was then added and the mixture was refluxed for 45 minutes.

4 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 1% hydrochloric acid solution, water, 10% sodium carbonate solution and water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from methanol afforded A -androsten-3- one-165,17/3-dicarboxylic acid imide.

Upon oxidation by the same technique of N-propyl-A androsten-3fl-ol-16,8,175-dicarboxylic acid imide, N-(N', N-diethylaminoethyl)-A androsten 3p3-o1-16B,17B dicarboxylic acid imide, N-phenyl-A -androsten-318-01-l6B, 17B-dicarboxylic acid imide, there were correspondingly formed A -androsten-3-one-l6p,17B-dicarboxylic acid imide, N-propyl-A -androsten-3-one-16p ,175 dicarboxylic acid imide, N-(N',N'-diethylaminoethyl)-A -androsten-3- one-165,17l3-dicarboxylic acid imide and N-phenyl-M- androsten-3-one-163,17,8-dicarboxylic acid imide.

Example X A solution of 800 mg. of A -androsten-3-one-163,175- dicarboxylic acid imide in 40 cc. of ethyl acetate was shaken with 50 mg. of 5% palladium-charcoal catalyst in a hydrogen atmosphere, until 1 mol. of gas was consumed. The catalyst was filtered off and the filtrate evaporated to dryness. Recrystallization from methanol-benzene afforded androstan-3-one-16,8,17,8-dicarboxylic acid imide. Following the same technique were hydrogenated N-propyl-A -androsten-3-one-163,17,8-dicarboxylic acid imide, N-(N,N-diethylaminoethyl)-A -androsten-3 one 16,8, 17fl-dicarboxy1ic acid imide, N-phenyl-A androsten-3-or1e- 16,8,17B-dicarboxylic acid imide giving respectively androstan-3-one-166,17fi-dicarboxylic acid imide, N-propylandrostan-3-one-16,8,17fi-dicarboxylic acid imide, N-(N', N-diethylaminoethyl)-androstan-3 one 165,17}? dicarboxylic acid imide and N-phenyl-androstan-3one-16p 17fi-dicarboxylic acid imide.

Example X1 800 mg. of A -androsten-3/3-ol-16,8,17,3-dicarboxylic acid imide were hydrogenated following the technique described in Example X, giving androsten-350L165,17,6-dicarboxylic acid imide.

When applying this procedure to N-propyl-A -androsten- 3,8-01-16/5,17,6-dicarboxylic acid imide, N-(N',N-diethyl aminoethyl)-A -androsten-3B-ol-16,8,17,5-dicarboxylic acid imide, N-phenyl-A -androsten-31301-165,175-dicarboxylic acid imide, there were correspondingly formed androstan- 3/3-o1-16l3,17B-dicarboxylic acid imide, N-propyl-androstan-3fl-ol-16fl,l7,B-dicarboxylic acid imide, N-(N,N-diethylarninoethyl)-androstan 3fl-ol-16[3,l7[3 dicarboxylic acid imide and N-phenyl-androstan-3,8-01-165,17,B-dicarboxylic acid imide.

Example XII 500 mg. of A -androsten-3fi-ol-16,8,17,8-dicarboxylic acid imide in 5 cc. of pyridine were treated with 1 cc. of propionic anhydride. The reaction mixture was left overnight at room temperature, then poured into ice water, the formed precipitate filtered 0E, washed with water and dried. Recrystallization from acetone-hexane afforded A androsten-3l3-ol-l 65,17,8-dicarboxylic acid imide 3-propionate.

Following the above technique were treated the starting materials listed below, with the acylating agent indicated, furnishing the corresponding products hereinafter set forth.

Starting compound Acylating agent Product A -androsten-iifl-olcaproic anhydride 3-caproate of A acid imide. 16B,17fl-dicarb0xylic acid imide.

Do l cyclopentylpropl- 3-cyclopentylpropioonic anhydn'de. nate of A -androsteu-3B-ol-16B,17fldicarboxylic acid imide.

N-propyl-N-androstenbenzoyl ch1oride B-bcnzoate of N- 3B-0l-16B,l7fl-dicarpropyl-A -androboxylic acid imide. stem-3 8014612175- dicarboxylic acid imide. Do propionic anhy- 3-propionate of N- dride. propyl-A -andro- Sten-3B-0l-16fl,175- dicarboxylic acid irnid-e. N (N N-diethy1amicaproic anhydride..- 3-caproate of N- noethyD-N-andro- (N,N-diethylamisten-3B-ol-16B,17flnoethyD-M-androdicarb oxylic acid sten-3B-0L16BJ7B- imide. dicarboxylic acid imide. N- (N,N-dicthy1a1nicyclopentylpropi- 3-cyclopenty1propionoethyD-N-androonic anhydride. nate of N-(N N- sten-3B-ol-16fl,17- diethylaminoethyD- dicarboxylic acid. N-androstcn-SB-ol- 168,17/3-dicarboxyl1c acid imide. androstan-3B-o1-16fl,17flpropionic anhy- 3-pr0pionate of andicarboxylic acid dride. drostan-3B-oiimide. 163,17B-dicarboxy1ic acid imide. D0 cyclopentylpropi- 3cyclopentylpr0pioonic anhydrid e. nate oi androstan- 3B-ol-16 8,17B-dicarboxylic acid imide. S-caproate of N- (N,N-diethy1aminoethyl)-audrostan-3B-ol-16/9J7fldicarboxylic acid im e.

S-benzoate of N- (N ,N-diethylaminocthyD-androstan-3fl-ol-16B,17fidicarboxylic acid imide.

3-propionate of N- phenyl-androstan- 3B-ol-16BJ76-dicarboxylic acid imide.

3-benzoate of N- phenyl-androstan- 3B-ol-16B,17fl'dicar boxylic acid imide.

N- (N ,N'-diethylam1- noethyD-androstan- 3B-o1-16fl,17B-dicarboxylic acid imide.

caproic anhydride.

Do beuzoyl chloride N -phenyl-androstan- 3B-0l-l6/3,17B-dicarboxylic acid imide.

propionic anhydride benzoyl chloride"..-

Example XIII By substituting in the method of Example IV the propylamine by other alkylamines such as methylamine, ethylamine or heptylamine, there was obtained the corresponding N-methyl, N-ethyl, and N-heptyl derivatives of A -androsten-3/S-ol-16,8,17,8-dicarboxylic acid imide 3- acetate which upon selective saponification by the method described in Example VIII were transformed into the corresponding free 3,3-alcohols.

By following the technique described in Example IX the thus :formed 3B-alcohols were oxidized to the corresponding 3-ketones, namely the N-methyl, N-ethyl and N-hepty-l derivatives of A -androstene-3-one-16fi,173-dicarboxylic acid imide.

Example XIV By substituting in Example VI the aniline by benzylamine or phenethylamine, there were obtained the corresponding N-benzyl and N-phenethyl derivatives.

7 I claim: 1. A compound selected from the group consisting of the following formula:

=ON-R1 wherein Z is selected from the group consisting of a double bond between 0-4 and C- and a saturated linkage between 0-4 and C-5 and R is selected from the group consisting of hydrogen, alkyl, dialkylaminoalkyl, aryl and aralkyl radicals each containing up to 8 carbon atoms. I

2. M androsten-B-one-l65,1713-dicarboxylic acid imide.

3. N-(NQNaiiethylaminoethyl)-A -androsten 3 one- 165,17B-dicarboxylic acid imide.

4. N-phenyl-A -androsten-3one-16,3,175 dicarboxylic acid imide.

5. Androstan-3-one-16,B,17B-dicarboxylic acid imide.

6. N propyl-androstan-3-one-165,17B-dicarboxylic acid imide.

7. A compound selected from the group consisting of the following fiormula:

a l 8 between C5 and C6; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, alkyl, dialkylaminoalkyl, a ryl and aralkyl radicals each containing up to 8 carbon atoms.

8. Androstan-3/8-ol-16 8,17p-dicarboxylic acid imide.

9. Nwpropylaandrostan-fi,B-ol-16 6,l7fi-dicarboxylic acid imide.

11. The 3-acetate of A -androsten-3 3-ol-165,17B-dicarboxy-lie acid imide.

12. The 3-propionate of N-propyl-A -androsten-3fl-ol- 16,8,17fi-dicarboxylic acid imide.

13. The 3-caproate of N-(N',N-diethy1aminoethyl)-A androsten-Sfi-ol-IQB,l7fidicarboxylic acid imide.

14. The S-propionate of N-pheny1-androstan-3 5-01-1653 17,8-dicarboxylic acid imide.

15. The B-benzoate of N-phenyl-androstan-3fi-ol-16/3, l7fi-dicarboxylic acid imide.

l6. A -androsten-3B-ol-16 3,l7fi-dicarboxylic acid.

17. The acetate of A -androsten-35-ol-16B,17,8-dicarboxylic acid anhydride.

18. A process for the production of androstan-l6fi,17,8- dicarboxy lic acid imide derivatives which comprises treating the corresponding 16ot-cyano-pregnan-20-one compound with an alkali metal hypohalogenite, hydrolyzing the 1a-cyano-androstan-l6,6-carboxylic acid thus formed in a basic medium, refluxing the obtained dicarboxylic acid with an acid anhydride and treating the formed steroid anhydride with a primary amine selected from the group consisting of alkylamine, dialkylaminoalkylamine, arylamine and aralkyyamine each containing up to 8 carbon atoms and ammonia.

19. The process of claim 18 wherein the alkali metal hypohalogenite is sodium hypobromite, the basic medium is dilute methanolic potassium hydroxide, the anhydride is acetic anhydride and the amine is propylamine.

No reference cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FOLLOWING FORMULA: 